In recent years, the discovery of both histone proteins and nucleosomal DNA as molecular targets for anticancer drugs opened a new questions about the molecular determinants underlying their biological effects. Organometallic complexes, which are particularly effective against different cancers, have been shown to exert their action by targeting both constituents of chromatin, chromosomal DNA and the associated histone proteins. Here, we combine X-ray crystallography and molecular simulations to reveal the molecular mechanism of binding of novel and potent Ru(II)-arene anticancer agents, based on the [Ru(II)(η6-arene)Cl(ethylene-diamine)] (RAED) compound. Molecular simulations at both the classical and hybrid quantum mechanics/molecular mechanics (QM/MM) levels reveal a peculiar mechanism of binding at the level of the nucleosomal DNA, which is not observed in canonical double-stranded DNAs. Indeed, due to the structural characteristics of the nucleosomal DNA and to the distinct coordination geometry of Ruthenium-arene complexes, our compounds circumvent the typical intercalative binding modes of DNA binders, resulting instead in a selective semi-intercalation of a nucleosomal guanine. For contrast, the compounds do not assume this specific binding mode in canonical double-stranded DNA (free DNA), exemplifying the difference in molecular action of anticancer compounds on free DNA versus compacted DNA. This is a crucial point, considering that the majority of the DNA in cells assumes a packed conformation, as being compacted in chromatin. Overall, this work contributes in deciphering the mechanism of action of novel anticancer agents at a chromatin level and suggests nucleosomes as key chemotherapeutic targets, with important insights for the development of new drug discovery strategies.

Molecular mechanism of chromatin targeting by potent rutenium-arene anticancer agents acting at the nucleosome core particle

251st National Meeting (2016)

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